1. Field of the Invention
This invention relates to the use of an in vivo electrochemical method (also called an in vivo voltammetric method or voltammetry) to measure the amounts of biogenic chemicals present in the body and brain of an animal or a human being. More particularly, it relates to the use of in vivo semiderivative voltammetric measurements of biogenic chemicals, particularly neurotransmitters, such as amines, amine metabolites, ascorbic acid, amino acids and neuropeptides produced in reaction to psychopharmacological agents and neuropsychopharmacological agents such as analgesics, antipsychotic drugs, antidepressants, and other modulators of brain and peripheral neurochemistry in diseased and healthy states.
2. Discussion of Background
It has been known to those possessing ordinary skill in the art that it is possible to measure certain limited types of biogenic chemicals using in vivo electrochemistry in the brains and suborgans of nonhuman primates and other animals. This measurement has been accomplished using such facets of electrochemical measurements as chronoamperometry, differential pulse voltammetry, double differential pulse voltammetry, linear scan voltammetry, and semiderivative voltammetry. In all of these methods, a working electrode, a reference electrode and an auxiliary electrode are attached to the brain or other organ of the animal to be studied. A controlled potential is applied to the working electrode and the current passing between the working electrode and the reference electrode is monitored as a signal and used to measure basal neurotransmitter release and any alterations in brain neurochemistry after pharmacological manipulation with drugs and other compounds and/or after a diseased state such as schizophrenia or Alzheimer's has been induced or mimicked. The signal is directly related to the chemical concentration of the neurotransmitter released from or through or taken up by or through the neuronal brain membrane (extracellularly) or the synaptic vesicles or other relevant organelles or cytoplasm (intracellularly). The mechanism of action can be presynaptic, or possibly postsynaptic and each signal represents an instantaneous readout of rate of neuronal mechanism. The signal may also be related to inhibition of normal reuptake of neurotransmitter at the neuronal membrane and may be a summation of release and reuptake processes, especially during treatment. The prior art teaches that this current is an anodic (oxidation) current, based on scientific principle. This signal is recorded as a graph indicating change in current with respect to time (chronoamperogram) or voltage (voltammogram).
It is known that voltammetric measurements can be used to detect certain biogenic substances in the brain of rats Kissinger, P. T.; Hart, J. B.; Adams, R. N.; "Voltammetry in Brain Tissue--A New Neurophysiological Measurement", Brain Research, 55 (1973), p. 209.!. Other researchers have also detected signals in the brains of living rats, as follows: McCreery, et al., Brain Res. Vol. 73 (1974), p. 23; Gonon, et al., Brain Res. Vol. 223 (1981), p. 69; Lane, et al., J. Electroanal. Chem., Vol. 95(1979), p. 117; Clemens and Phebus, Brain Res., Vol 267(1983), p. 183 and Millar, et al., Eur. J. Pharmacol. Vol. 109(1985), p. 341.
There has been, however, little or no description of circuitry for in vivo electrochemical circuits. However, certain improvements have been made for in vitro voltammetric measurements since the linear scan for in vivo electrochemistry method was first described for measuring biogenic chemicals. one such improvement was the in vitro processing of the linear scan current signal as the first half-derivative of the linear signal Oldham, "Analytical Chemistry" Vol. 45 (1973) p. 39 and U.S. Pat. No. 3,868,578; Kanazawa, U.S. Pat. No. 4,449,552!. However, neither Oldham nor Kanazawa describe circuitry applicable for detection of organic materials in living organisms. Although they describe oxidation and reduction reaction species, they do not describe cathodic (reduction) currents in vivo. For the purposes of this application, cathodic current is defined as current based on the acquisition of electrons by neurochemicals within the organ or suborgan and flowing away from and/or on an indicator electrode situated within the organ or suborgan. Anodic current is defined as current based on the loss of electrons by neurochemicals in the organ or suborgan and flowing toward and/or on an indicator electrode situated within the organ or suborgan.
When applied to the brain, or other body organs, this type of processing (the first half derivative of the linear signal) should result in a semidifferentiated voltammogram having sharper peaks, which then allows greater separation between peaks representing chemical substances and which are easier to read than previous, linear voltammograms. The older conventional methods did not allow sharply defined individual detection of amines because of similar electrochemical potentials for biogenic amines set by the catechol moiety of the amines. Chronoamperometry, for example, does not allow any direct, individual and simultaneous detection of the biogenic amines. Semiderivation or semidifferentiation of the signal briefly allowed somewhat better detection. Many practitioners, however, have found it difficult or impossible to obtain reproducible measurements routinely using what is known as the in vivo electrochemistry technique of semiderivative or semidifferential voltammetry.
Although telemetric devices have been produced in the past, as described in U.S. Pat. No. 4,424,812 (Lesnick) and U.S. Pat. No. 3,882,277 (DePedro), telemetric devices for monitoring brain signals have not been described. Neither of these patents describe monitoring signals produced electrochemically either in vivo, in vitro or in situ.
The wisdom of the prior art indicates that an oxidation current, or anodic current, should be used to detect biochemical species in the brain. Previous researchers assumed that in living systems, all chemical species which could be detected by electrochemical signals were converted into stable oxidized species. Most of the previous researchers also assumed that all biogenic chemical reactions produced oxidized species without producing stable reduced species. These assumptions have provided only a limited tool for diagnosing the mental and physiological states of living organisms, as only a limited number of biogenic chemicals can be detected using prior art methods. In U.S. Pat. No. 4,883,057, we described a cathodic current for measuring biogenic chemicals with a semiderivative circuit in vivo and in vitro. In the context of this Application, we further describe several new inventive probes, electrodes, microelectrodes or sensors which can be utilized in vivo and in vitro for anodic and cathodic currents in a variety of electrochemical circuits.